Trial Outcomes & Findings for 1/2-Dopaminergic Dysfunction in Late-Life Depression (The D3 Study) (NCT NCT04493320)

NCT ID: NCT04493320

Last Updated: 2023-05-22

Results Overview

In this task participants decide whether to work harder for a larger reward (high number of finger presses with their pinky) or expend less energy (low number of presses with a dominant index finger) for a lesser reward, with lower rewards being $1 dollar and higher rewards ranging from $1.20 to $5. Participants receive information about the probability of winning on each trial regardless of their pick and one trial from each run is randomly picked for payout. The primary output on this task is the percentage of time participants choose the high cost / high reward option on the EEfRT. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations. This task was not completed following Step 2 of the study, so there are no EEfRT data reported for change in task performance following Step 2.

• Recruitment status: TERMINATED
• Study phase: PHASE4
• Target enrollment: 5 participants
• Primary outcome timeframe: Change from Baseline to 3 weeks (post Step 1)
• Results posted on: 2023-05-22

Participant Flow

In total, 5 depressed subjects were enrolled. Of the 5 enrolled, 1 subject was found to be ineligible. Thus, 5 participants enrolled and 4 were assigned to a treatment group and began the study.

Participant milestones

Measure	L-DOPA, Then Placebo Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Overall Study STARTED	2	2
Overall Study COMPLETED	1	1
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

1/2-Dopaminergic Dysfunction in Late-Life Depression (The D3 Study)

Baseline characteristics by cohort

Measure	L-DOPA, Then Placebo n=2 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=2 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Total n=4 Participants Total of all reporting groups
Age, Continuous	74.5 years STANDARD_DEVIATION 16.3 • n=5 Participants	65.5 years STANDARD_DEVIATION 7.8 • n=7 Participants	70.0 years STANDARD_DEVIATION 11.6 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Montgomery Asberg Depression Rating Scale	24.5 units on a scale STANDARD_DEVIATION 5.0 • n=5 Participants	36.5 units on a scale STANDARD_DEVIATION 12.0 • n=7 Participants	25.5 units on a scale STANDARD_DEVIATION 7.6 • n=5 Participants
Clinical Global Impressions--Severity	5.0 units on a scale STANDARD_DEVIATION 0.0 • n=5 Participants	4.0 units on a scale STANDARD_DEVIATION 0.0 • n=7 Participants	4.3 units on a scale STANDARD_DEVIATION 0.6 • n=5 Participants
Quick Inventory for Depressive Symptomatology	10.0 units on a scale STANDARD_DEVIATION 0.0 • n=5 Participants	15.0 units on a scale STANDARD_DEVIATION 4.2 • n=7 Participants	13.3 units on a scale STANDARD_DEVIATION 4.2 • n=5 Participants

PRIMARY outcome

Timeframe: Change from Baseline to 3 weeks (post Step 1)

Population: Participants with Baseline and Week 3 data available were analyzed

In this task participants decide whether to work harder for a larger reward (high number of finger presses with their pinky) or expend less energy (low number of presses with a dominant index finger) for a lesser reward, with lower rewards being $1 dollar and higher rewards ranging from $1.20 to $5. Participants receive information about the probability of winning on each trial regardless of their pick and one trial from each run is randomly picked for payout. The primary output on this task is the percentage of time participants choose the high cost / high reward option on the EEfRT. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

This task was not completed following Step 2 of the study, so there are no EEfRT data reported for change in task performance following Step 2.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=2 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Effort Expenditure for Rewards Task (EEfRT) Following Step 1	0.18 percentage of high effort choices Standard Deviation NA Standard Deviation is not calculable for 1 participant.	0.0 percentage of high effort choices Standard Deviation 0.0

PRIMARY outcome

Timeframe: Change from Baseline to 3 weeks (post Step 1)

Population: Participants with Baseline and Week 3 data available were analyzed

The Digit Symbol test is a neuropsychological test measuring information processing speed. It consists of digit-symbol pairs (e.g. 1/-,2/┴ ... 7/Λ,8/X,9/=) followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time is measured. Score ranges from 0-133, with higher scores indicating higher information processing speed. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=2 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=2 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Digit Symbol Test Following Step 1	-0.5 Number of items correctly completed Standard Deviation 2.1	9.0 Number of items correctly completed Standard Deviation 7.1

PRIMARY outcome

Timeframe: Change from Week 3 to Week 7 (post-Step 2)

Population: Participants with Week 3 and Week 7 data available were analyzed

The Digit Symbol test is a neuropsychological test measuring information processing speed. It consists of digit-symbol pairs (e.g. 1/-,2/┴ ... 7/Λ,8/X,9/=) followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time is measured. Score ranges from 0-133, with higher scores indicating higher information processing speed. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=1 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Digit Symbol Test Following Step 2	5.0 Number of items correctly completed	4.0 Number of items correctly completed

PRIMARY outcome

Timeframe: Change from Baseline to 3 weeks (post Step 1)

Population: Participants with Baseline and Week 3 data available were analyzed

This test required participants to identify whether two visual patterns are the "same" or "not the same" (responses were made by pressing a "yes" or "no" button). Patterns were either identical or varied on one of three dimensions: color (all ages), adding/taking something away (all ages), or one versus many. Scores reflect the number of correct items completed in 90 s, with scores ranging from a minimum of 0 to a maximum of 30. Items were designed to minimize the number of errors that were made. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=2 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=2 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Pattern Comparison Test Following Step 1	-1.0 Number of items correctly completed Standard Deviation 1.4	1.75 Number of items correctly completed Standard Deviation 1.1

PRIMARY outcome

Timeframe: Change from Week 3 to Week 7 (post-Step 2)

Population: Participants with Week 3 and Week 7 data available were analyzed

This test required participants to identify whether two visual patterns are the "same" or "not the same" (responses were made by pressing a "yes" or "no" button). Patterns were either identical or varied on one of three dimensions: color (all ages), adding/taking something away (all ages), or one versus many. Scores reflect the number of correct items completed in 90 s, with scores ranging from a minimum of 0 to a maximum of 30. Items were designed to minimize the number of errors that were made. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=1 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Pattern Comparison Test Following Step 2	1.0 Number of items correctly completed	-3.5 Number of items correctly completed

PRIMARY outcome

Timeframe: Change from Baseline to 3 weeks (post Step 1)

Population: Participants with Baseline and Week 3 data available were analyzed

Subjects were asked to determine whether two strings of letters are the same or different. There are 3 pages and the subject is given 30 seconds per page. Scoring is based on the number answered correctly. Scores range from 0 to 21, with the higher the number, the better the score. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=2 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=2 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Letter Comparison Test Following Step 1	-0.5 Number of items correctly completed Standard Deviation 0.0	-0.25 Number of items correctly completed Standard Deviation 2.5

PRIMARY outcome

Timeframe: Change from Week 3 to Week 7 (post-Step 2)

Population: Participants with Week 3 and Week 7 data available were analyzed

Subjects were asked to determine whether two strings of letters are the same or different. There are 3 pages and the subject is given 30 seconds per page. Scoring is based on the number answered correctly. Scores range from 0 to 21, with the higher the number, the better the score. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=1 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Letter Comparison Test Following Step 2	0.5 Number of items correctly completed	-1.5 Number of items correctly completed

PRIMARY outcome

Timeframe: Change from Baseline to 3 weeks (post Step 1)

Population: Participants with Baseline and Week 3 data available were analyzed

Patients' gait was assessed as walking speed in cm/s on a 15' walking course. Patients walked at their usual or normal speed for a total of 27' (starting and ending at a point 6 feet prior to and after the 15' course to eliminate acceleration and deceleration effects). Two trials were completed, and gait speed was based on the average of 2 trials. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=2 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=2 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Single Task Gait Speed Test Following Step 1	4.6 cm/s Standard Deviation 5.9	11.9 cm/s Standard Deviation 11.2

PRIMARY outcome

Timeframe: Change from Week 3 to Week 7 (post-Step 2)

Population: Participants with Week 3 and Week 7 data available were analyzed

Patients' gait was assessed as walking speed in cm/s on a 15' walking course. Patients walked at their usual or normal speed for a total of 27' (starting and ending at a point 6 feet prior to and after the 15' course to eliminate acceleration and deceleration effects). Two trials were completed, and gait speed was based on the average of 2 trials. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=1 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Single Task Gait Speed Test Following Step 2	-17.2 cm/s	7.0 cm/s

PRIMARY outcome

Timeframe: Baseline (prior to LDOPA or placebo administration)

Population: Participants who had a baseline \[18F\]-FDOPA PET scan

[18F]-FDOPA PET quantifies dopamine synthesis capacity in specific brain regions. Lower [18F]-FDOPA uptake in the striatum has been associated with increased depression severity and worse cognitive and motor function in patients. Because [18F]-FDOPA uptake may be sensitive to deficits in dopamine synthesis capacity in older depressed patients, in this study depressed participants at baseline underwent a PET scan to quantify relative [18F]-FDOPA influx rate in the nucleus accumbens bilaterally. Time activity curves (TACs) were extracted within the nucleus accumbens region of interest (ROI) as the average radioactivity in the ROI over time. The occipital lobe, which has the lowest dopamine concentration in the brain, was used as the "reference region" to yield the Kocc measure of [18F]-FDOPA influx rate. Higher [18F]-FDOPA influx rate (kocc) numbers indicate greater relative influx rate and therefore greater dopamine synthesis capacity.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
[18F]-FDOPA PET Measure in Striatal Region of Interest	0.0107 min^-1	—

SECONDARY outcome

Timeframe: Change from Baseline to 3 weeks (post Step 1)

Population: Participants with Baseline and Week 3 data available were analyzed

Secondary outcome measured by the total score of the clinician rated MADRS, a measure of depression severity. The MADRS total score range is 0-60, where higher scores indicate greater depression severity. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=2 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=2 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Montgomery Asberg Depression Rating Scale Following Step 1	-1.0 units on a scale Standard Deviation 9.9	-3.0 units on a scale Standard Deviation 2.8

SECONDARY outcome

Timeframe: Change from Week 4 to Week 7 (post-Step 2)

Population: Participants with Week 4 and Week 7 data available were analyzed

Secondary outcome measured by the total score of the clinician rated MADRS, a measure of depression severity. The MADRS total score range is 0-60, where higher scores indicate greater depression severity. In contrast to other measures, which were not available at Week 4, Week 4 was selected as the baseline for post-Step 2 change on the MADRS since it followed the taper period taking place between study Steps. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=1 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Montgomery Asberg Depression Rating Scale Following Step 2	4.0 units on a scale	2.0 units on a scale

SECONDARY outcome

Timeframe: Change from Baseline to 3 weeks (post Step 1)

Population: Participants with Baseline and Week 3 data available were analyzed

QIDS-16-item, a participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27, with higher scores indicative of greater severity. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=2 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Quick Inventory for Depressive Symptomatology (QIDS) Following Step 1	-1.0 units on a scale Standard Deviation 0.0	-5.0 units on a scale Standard Deviation 5.7

SECONDARY outcome

Timeframe: Change from Week 4 to Week 7 (post-Step 2)

QIDS-16-item, a participant-rated measure of depressive symptomatology. The total score ranges from 0 to 27, with higher scores indicative of greater severity. In contrast to other measures, which were not available at Week 4, Week 4 was selected as the baseline for post-Step 2 change on the QIDS since it followed the taper period taking place between study Steps. Because the full sample was not enrolled and the results are considered unreliable, no statistical analysis was performed other than calculating means and standard deviations.

Outcome measures

Measure	L-DOPA, Then Placebo n=1 Participants Step 1 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1 week taper period. Step 2 (3 Weeks): Participants will receive L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily	Placebo, Then L-DOPA n=1 Participants Step 1 (3 Weeks): Participants will receive 3 L-DOPA matching placebo tablets daily. Participants will then enter a 1-week taper period. Step 2 (3 Weeks): Participants will first receive 150 mg of L-DOPA daily in Week 1, 300 mg of L-DOPA in Week 2, and 450 mg L-DOPA in Week 3. Participants will then enter a 1-week taper period. Carbidopa/levodopa: 150-450mg carbidopa/levodopa 3 times daily Placebo: Carbidopa/levodopa-matched placebo tablet 3 times daily
Change in Quick Inventory for Depressive Symptomatology (QIDS) Following Step 2	-1.0 units on a scale	0.0 units on a scale

Adverse Events

L-DOPA

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	L-DOPA n=4 participants at risk This trial entailed the administration of either L-DOPA or placebo in Step 1, followed by crossover to the other treatment assignment in Step 2 (i.e., L-DOPA followed by placebo or placebo followed by L-DOPA). Adverse events are grouped here by treatment assignment (L-DOPA or placebo). This arm pertains to the administration of L-DOPA in Step 1 and Step 2 of the study.	Placebo n=3 participants at risk This trial entailed the administration of either L-DOPA or placebo in Step 1, followed by crossover to the other treatment assignment in Step 2 (i.e., L-DOPA followed by placebo or placebo followed by L-DOPA). Adverse events are grouped here by treatment assignment (L-DOPA or placebo). This arm pertains to the administration of placebo in Step 1 and Step 2 of the study.
Gastrointestinal disorders Diarrhea	25.0% 1/4 • Number of events 1 • Subjects were monitored over a period of 7 weeks.	0.00% 0/3 • Subjects were monitored over a period of 7 weeks.
Nervous system disorders Headache	25.0% 1/4 • Number of events 1 • Subjects were monitored over a period of 7 weeks.	0.00% 0/3 • Subjects were monitored over a period of 7 weeks.
Psychiatric disorders Insomnia	25.0% 1/4 • Number of events 1 • Subjects were monitored over a period of 7 weeks.	33.3% 1/3 • Number of events 2 • Subjects were monitored over a period of 7 weeks.
Vascular disorders Dizziness	25.0% 1/4 • Number of events 1 • Subjects were monitored over a period of 7 weeks.	33.3% 1/3 • Number of events 1 • Subjects were monitored over a period of 7 weeks.
Vascular disorders Increased blood pressure	25.0% 1/4 • Number of events 1 • Subjects were monitored over a period of 7 weeks.	0.00% 0/3 • Subjects were monitored over a period of 7 weeks.
General disorders Faintness	0.00% 0/4 • Subjects were monitored over a period of 7 weeks.	33.3% 1/3 • Number of events 1 • Subjects were monitored over a period of 7 weeks.
Psychiatric disorders Drowsiness	0.00% 0/4 • Subjects were monitored over a period of 7 weeks.	33.3% 1/3 • Number of events 1 • Subjects were monitored over a period of 7 weeks.
Gastrointestinal disorders Dry mouth	0.00% 0/4 • Subjects were monitored over a period of 7 weeks.	33.3% 1/3 • Number of events 1 • Subjects were monitored over a period of 7 weeks.

Additional Information

Dr. Bret Rutherford

New York State Psychiatric Institute

Phone: 646 774 8660

Email: bret.rutherford@nyspi.columbia.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place